Address for correspondence: Anna Hogendorf MD, PhD, Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna, 91-378 Lodz, Poland, e-mail: anna.hogendorf@gmail.com
Pachyonychia congenita type 1 (Jadassohn-Lewandowsky syndrome) – case report and literature review
Anna Hogendorf1, Agnieszka Cywińska-Bernas2, Andrzej Kaszuba3, Krzysztof Zeman2
1Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland Head: Prof. Wojciech Młynarski MD, PhD
2Department of Pediatrics and Clinical Immunology with Nephrology Division, Polish Mother's Memorial Hospital Research Institute, Medical University of Lodz, Poland
Head: Prof. Krzysztof Zeman MD, PhD
3Department of Dermatology and Pediatric Dermatology, Medical University of Lodz, Poland Head: Prof. Andrzej Kaszuba MD, PhD
Post Dermatol Alergol 2011; XXVIII, 4: 323–327
A b s t r a c t
Pachyonychia congenita (PC) is a rare genodermatosis of autosomal dominant pattern of inheritance, affecting nails, skin, oral mucosa, larynx, hair and teeth. The clinical phenotype is a result of a pathogenic mutation in one of the genes encoding keratins. Owing to recent clinical and molecular analyses of patients from the International Pachyonychia Congenita Research Registry it was possible to start clinical trial on gene therapy using small inter- fering RNA molecules to knock out the mutant keratin. This novel approach is opening up a new avenue for the treatment of genetic skin diseases. We report a case of a 9-year-old girl with pachyonychia congenita type 1 (PC-1), previously termed Jadassohn-Lewandowsky syndrome, suffering from the most frequent of the known mutations – KRT6aN172del.
Key words: nails, pachyonychia congenita, Jadassohn-Lewandowsky syndrome, siRNA.
Introduction
Pachyonychia congenita (PC) is an ultra-rare geno- dermatosis, of mainly autosomal pattern of inheritance, that typically begins in infancy [1, 2]. It is estimated that a few thousand individuals may be affected with PC worldwide [3].
The most striking clinical feature of PC is symmetrical thickening of all nails – hypertrophic nail dystrophy or pachyonychia – which is observed in over 90% of cases.
Characteristic changes in the nails include hyperkerato- sis of the nail bed, thickening of the nail plate and dis- tortion or curvature of the nail plate, which usually has a yellowish-grey colour. In 91-96% of cases of PC, variable degrees of a focal palmoplantar keratoderma are observed [4]. In the most severe clinical phenotypes deep plantar blisters may even be complicated by acro-osteolysis of bones [5, 6]. Therefore the disease is often debilitating, causing the patient to adopt a compulsory position while walking or to move with crutches, wheelchairs and oth- er walking aids [4, 7]. The other characteristic features of
PC include steatocystoma and pilosebaceous cyst forma- tion, keratosis pilaris and leukokeratosis (leukoplakia) of the oral mucosa and larynx that do not lead to a neo- plastic process. In infants laryngeal leukokeratosis may present as stridor and even lead to acute respiratory insuf- ficiency [8]. In adults glottal leukoplakia may result in chronic or recurrent hoarseness [4, 8]. In some patients hair abnormalities and natal teeth (teeth erupted at birth or shortly after birth) are also found [4].
The first description of the disease comes from Ire- land from 1685. It was included in a letter from Mr St.
George Ash to one of the Secretaries of the Royal Society, concerning an Irish girl who had “several horns growing on her body” [9]. In 1716 “monstrous nails” were a sub- ject of a doctoral dissertation by Carl Musaeus [10].
The term “pachyonychia congenita” meaning “thick nails since birth” was introduced in 1906 by Jadassohn and Lewandowsky [11].
The disorder results from mutations in genes encod- ing keratins K6a, K6b, K16 or K17 – proteins that form the
cytoskeleton of epithelial cells [12-14]. In most cases the mutations are caused by small deletions and single nucleotide changes of an autosomal dominant pattern of inheritance. However, a few reports on recessive inheri- tance have also been published, mainly in offspring of consanguineous parents [15]. Spontaneous mutations appear to be relatively common (29%), according to liter- ature reporting a negative family history [16].
The current classification distinguishes two types of the disease. The PC-1 clinical phenotype, or Jadassohn- Lewandowsky syndrome, is associated with mutation in K6a and K16 which is expressed in palmoplantar epi- dermis, mucosal epithelia and follicular keratinocytes.
Therefore PC-1 is characterized by pachyonychia with focal palmoplantar keratoderma, follicular hyperkerato- sis and oral and laryngeal leukokeratosis, more pro- nounced than in pachyonychia congenita type 2 (PC-2).
In PC-2, also known as Murray-Jackson-Lawler syndrome, there are widespread pilosebaceous cysts, bushy eye- brows and hair abnormalities such as pili torti (twisted hair) or alopecia and additional features such as natal teeth. They are caused by mutations in K6b and K17 expressed in the pilosebaceous unit and basal appendageal keratinocytes [17, 18].
Case report
A 9-year-old girl with suspected Jadassohn-Lewan - dowsky syndrome was referred to the Department of Pediatrics and Clinical Immunology, Medical University of Lodz, for evaluation of a variant of precocious puberty (isolated breast enlargement or thelarche praecox).
All 20 of her fingernails and toenails were thickened, dystrophic, of yellowish-grey colour, with massive sub- ungual hyperkeratosis. The patient could barely walk because of painful callosities and blistering present on her soles. They were hard, non-erythematous and accen- tuated in weight-bearing points. Severe keratosis pilaris was present especially on the arms, hips and back. These
lesions were also widespread across the trunk and the face (mainly on the forehead). Keratotic spikes on the elbows and knees were also observed. Her palms and soles were sweaty. The examination of the mouth revealed angular cheilitis and slight leukokeratosis of the edges of the tongue.
Signs of puberty were also present – thelarche (T) III, pubarche (P) II/III on Tunner’s scale. Ultrasound exami- nation of female internal reproductive organs showed evi- dence of estrogenic stimulation and no masses. The serum concentration of follicle-stimulating hormone (FSH) and oestradiol was above the normal level for the age. Bone age according to the method of Greulich and Pyle was estimated to be for 12 years. She had no neurological symptoms.
The most severe and annoying symptoms of all she complained of was a sharp pain on walking, associated with breaking of blisters under calluses, which sometimes made normal functioning impossible. There were times when she was forced to adopt a compulsory position – even to move on her knees. It occurred usually after extended periods of standing or walking, especially on an uneven surface or during warm weather. Frequent adop- tion of an unnatural position led to the development of faulty posture.
Thick nail plates created an obvious aesthetic prob- lem, but due to frequent injuries and recurrent bacterial and fungal infections, they were also a cause of physical suffering. After application of regular professional debridgement in a specialized medical cosmetic studio, fingernails and toenails were well maintained, shortly cut and covered with nail enamel, but even then they still looked “monstrous”. There were other complaints such as excessive ear wax production and sweating, persistent dandruff and recurrent hoarseness of voice.
The history revealed that thickened, discoloured nails were first noticed on the 3rdday of her life. A few days later, small ulceration and a circumscribed thick white patch on the tongue was spotted (leukoplakia?) and treat-
Fig. 1. Hypertrophic nail dystrophy Fig. 2. Follicular hyperkeratosis and keratotic spikes
ed as thrush. She was breastfed one month only due to feeding difficulties (painful suckling?). During the first years of life the first episodes of recurrent painful ery- thematous swelling, bleeding of the nail folds and pyo- genic infections were reported. Painful callosities and blistering on the soles were first noticed when she start- ed to walk. At that time, thickened white patches in her mouth were noticed on the tongue and inside the lips and were treated by the family doctor as a yeast infec- tion. Breast development was first observed when the girl was 1 year and 3 months.
Finally, when she was 9, on the basis of physical exam- ination, radiograph of the carpal bones, and hormonal studies the girl was diagnosed as having a variant of ear- ly puberty (thelarche praecox) with no indication for hor- monal inhibition of puberty. The girl was born to non-con- sanguineous parents. None of her family members had similar abnormalities.
Searching the literature in order to find data regard- ing pachyonychia congenita led us to The Pachyonychia Congenita Project (PC Project) website and the Interna- tional Pachyonychia Congenita Research Registry (IPCRR) www.pachyonychia.org, from where we learned about the possibility of free genetic testing.
“PC Project”, which is a non-profit USA public char- ity, was founded in November 2003 and supports clini- cal and research activities related to the treatment of pachyonychia congenita. The recruitment of participat- ing patients is primarily self-referral to the web-based registry (http://www.pachyonychia.org/Registry.html) or a direct referral by a physician. Medical history ques- tionnaires and a series of standard photographs should also be provided. The next step is to consult the patient by telephone with one of the top dermatologists spe- cializing in PC, in order to establish the diagnosis and determine the appropriateness of free-of-charge genet- ic testing.
The mutation status of our patient was determined after sending a mouth swab by sequence analysis in a research laboratory of the Epithelial Genetic Group, Human Genetics Unit, Dundee University, Scotland and was verified in the clinical laboratory of GeneDx (Gaithers- burg, Maryland, USA). The molecular analysis revealed that the mutation found in our patient was KRT6aN172del – a heterozygous deletion of 3 nucleotides (CAA) in exon 1 of the KRT6a gene located on 12q13 chromosome and sit- uated in a highly conserved helix boundary motif of the K6a protein essential for end-to-end overlapping during keratin filament assembly [19]. Almost all of the already identified mutations occur at this site [20].
Discussion
We describe an exceptional case of pachyonychia con- genita and a variant of precocious puberty. Such coexis- tence has not been described in the literature previous-
ly. However, on the basis of current knowledge it should be clearly stated that premature breast development or premature thelarche is not a phenotypic feature of PC.
Among other symptoms previously incorrectly ascribed to PC were deafness, mental disability, cataract forma- tion, corneal dyskeratosis, skeletal abnormalities, patent ductus arteriosus, supernumerary digits and delayed development of genitalia. They are extremely rare and, as in this case, rather not related to PC [20].
The premature thelarche observed in our patient is a benign, usually transient condition of isolated breast development, with no other signs of sexual maturation in girls under 7 or 8 years of age. Growth and osseous maturation are normal or slightly advanced. Menarche occurs at the expected age. Plasma basal levels of FSH and their responses to gonadotropin-releasing hormone stimulation are greater than those seen in normal con- trols. In contrast, children with true precocious puberty secrete predominantly luteinizing hormone [21].
Owing to PC Project the International Pachyonychia Congenita Consortium, a collaborative team of scientists and clinicians, was established in 2004. Since then, enor- mous progress in the research on PC has been made. The project includes more than 928 patients from around the world and 66 mutations and clinical phenotypes of 445 people from 200 families have already been studied.
Pachyonychia congenita has become exceptional among thousands of other genetically defined disorders because the afflicted patients have a chance of undergoing a dis- ease-targeted therapy.
In 2008, the first clinical trial on humans involving the use of siRNA (small interfering RNA) was started. siRNA are a new class of RNA inhibitors that post-transcription- ally inhibit gene expression of a mutant gene responsible for PC-1 symptoms.
These 20-25 nucleotide-long double-stranded RNAs are homological to a sequence of targeted mutant mRNA.
They bind to a protein of ribonuclease activity and cut Fig. 3. Plantar keratoderma
mutated RNA into pieces, causing knock out of the mutat- ed protein – in this case keratin K6a. The siRNA called TD101 specifically and potently target mutated allele KRT6aN171K without affecting wild type K6a mRNA [22- 24]. As shown in knockout mouse studies, the two major genes K6a and K6b express functional redundancy. This means that knocking out one of these keratins has little or no phenotypic consequences. The complete knock-out of K6a leads to compensative K6b or other keratin expres- sion without development of symptoms of the disease [25-27]. Such a situation occurs in 1 of 4000 healthy peo- ple [28].
Starting in 2008, the first-in-human mutation-target- ed phase Ib clinical trial for the treatment of PC investi- gated the safety and tolerability of increasing the volume and concentration of intra-lesional siRNA injections. It was a split-body, double-blind trial. The subject was an adult PC-1 patient. The drug was injected into the plan- tar keratoderma of one foot and the vehicle into kerato- derma of the other foot. No adverse events occurred dur- ing the trial or in the three-month washout period. The patient’s subjective assessment and the physician’s clin- ical efficacy measures showed regression in the siRNA- treated callus only. It began to fall away and healthy pink skin was revealed underneath. The skin was remarkably non-tender to palpation, which had never been observed by the patient previously. If siRNA proves to be effective in the treatment of PC, there will be a chance of devel- oping effective treatment of dominant genetic skin dis- eases and many other disorders [26].
Until the siRNA gene therapy is available, the current treatment options may only relieve symptoms. They can be divided into mechanical, surgical, chemical and phar- macological. In general, the therapy should be individu- alized because the symptoms and pain levels vary in PC patients, even among members of the same family and identical mutations. Although the exquisitely sensitive calluses cannot be removed effectively and completely, patients usually use razor blades or pumice stones to groom them. The pain experienced during grooming can be reduced by the application of oral non-steroidal anti- inflammatory drugs. Emollients are also reported to be somewhat effective for pain and appearance. Ointments and creams containing a high percentage of humectants and keratolytics, such as urea and Lac-hydrin, are also recommended. Mechanical removal of the excessive keratin in thick nails can be done using hand tools such as clippers, curettes, rasps, files, paring knives, pumice stones, electrical hand-held grinders, polishers, and sanders. It should be done routinely, after bathing, to help alleviate the pain and facilitate removal of the outer keratin layers. In order to soften the nails, pastes of 20-40% urea or 15-20% salicylic acid content should be used, especially if applied overnight [27]. It has also been reported by Swartling et al. that botulinum toxin injec- tions reduce hyperkeratosis and hyperhidrosis of palms
and soles [28]. Oral antihistamines, topical steroids and anaesthetics are effective to some extent in itching relief.
Cysts are managed by excision, incision, drainage or hyfre- cation and diathermy. The use of oral and/or topical retinoids is somewhat effective for appearance but not in all patients. However, this treatment should be recommended individually with regard to benefits and side effects incommensurable with expectations [27].
Nail infections should be treated with topical and sys- temic antibiotics [29]. The culture of the mucous mem- brane leukokeratotic lesions frequently shows the pres- ence of Candida albicans strain of fungi. Unfortunately, long-term anti-fungal treatment fails to give desirable results and does not improve the mucous membrane appearance in the majority of cases.
Conclusions
The presented girl is the first Polish PC patient referred to IPCRR and whose disease was confirmed by genetic testing. The mutation turned out to be the most common in the IPCRR patients, which gives a chance of genetic therapy. Owing to PC Project the patient and her family were invited to the Pachyonychia Congenita Patient Sup- port Meeting in Pitlochry, Scotland and had an opportu- nity to meet other children with PC as well as scientists and clinicians who work on finding a cure for this rare, debilitating disease.
We suggest that physicians treating patients with PC refer them to the PC Project website, www.pachyony- chia.org, for up-to-date suggestions regarding manage- ment of PC and support.
Acknowledgments
The authors would like to thank Mary Schwartz, Pachyonychia Congenita Project, Salt Lake City, Utah, USA;
Frances Smith PhD, Human Genetics Unit, Ninewells Hos- pital and Medical School University of Dundee, Dundee, UK; and Sancy Leachman MD, PhD, Department of Der- matology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA for their help and cooperation.
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